As CRISPR emerges, re­searchers spot­light pos­i­tive ef­fects in pre­na­tal gene edit­ing treat­ment for mice

In a break­through for the buzzing world of CRISPR re­search, a team of sci­en­tists has demon­strat­ed a use of the gene edit­ing tool to treat a ge­net­ic dis­ease in mice be­fore they are born.

The proof-of-con­cept study brings them one step clos­er — though still miles away — to the ul­ti­mate goal of treat­ing se­vere hu­man dis­eases di­ag­nosed ear­ly in preg­nan­cy, ac­cord­ing to the re­searchers from Chil­dren’s Hos­pi­tal of Philadel­phia and the Perel­man School of Med­i­cine at the Uni­ver­si­ty of Penn­syl­va­nia.

William Per­an­teau

“A sig­nif­i­cant amount of work needs to be done be­fore pre­na­tal gene edit­ing can be trans­lat­ed to the clin­ic,” said study co-leader William Per­an­teau, a pe­di­atric and fe­tal sur­geon in CHOP’s Cen­ter for Fe­tal Di­ag­no­sis and Treat­ment. “Nonethe­less, we are ex­cit­ed about the po­ten­tial of this ap­proach to treat ge­net­ic dis­eases of the liv­er and oth­er or­gans for which few ther­a­peu­tic op­tions ex­ist.”

For their study, pub­lished in Na­ture Med­i­cine, the team com­bined two dif­fer­ent tech­niques: Us­ing the well-known CRISPR-Cas9 com­pound as a guide, they fused an en­zyme to it that chem­i­cal­ly mod­i­fies the ge­net­ic code once the com­pound ar­rived at the spec­i­fied ge­net­ic lo­ca­tion. Dubbed base ed­i­tor 3, this method is de­scribed as po­ten­tial­ly safer than the cut-and-paste mod­el of reg­u­lar CRISPR-Cas9, which re­searchers have warned could cause off-tar­get ef­fects.

But be­fore they test­ed the tool on a group of mice en­gi­neered to de­vel­op the lethal liv­er dis­ease hered­i­tary ty­rosine­mia type 1 (HT1), the in­ves­ti­ga­tors first tried it out with the PC­SK9 gene — a cho­les­terol reg­u­la­tor now tar­get­ed by a new class of car­dio drugs — and showed that the fe­tus­es re­ceiv­ing this treat­ment were born with sig­nif­i­cant­ly low­er cho­les­terol lev­els.

Sim­i­lar­ly, the in­tend­ed ef­fect was ob­served in new­born mice which had a re­lat­ed gene — not the dis­ease-caus­ing one — dis­abled in utero: They “car­ried sta­ble amounts of edit­ed liv­er cells for up to three months af­ter the pre­na­tal treat­ment, with no ev­i­dence of un­want­ed, off-tar­get edit­ing at oth­er DNA sites” with “im­proved liv­er func­tion and pre­served sur­vival.”

In fact, they did even bet­ter than mice born with HT1 that are sub­se­quent­ly treat­ment with ni­tisi­none and di­et, the cur­rent stan­dard of care for in­fants with HT1.

The in­ves­ti­ga­tors re­main cau­tious­ly op­ti­mistic about their ear­ly work, al­ready test­ing al­ter­na­tive de­liv­ery sys­tems to the ade­n­ovirus vec­tors used in this ex­per­i­ment, as it’s been sug­gest­ed that ade­n­ovirus vec­tors, a main­stay in gene ther­a­py ex­per­i­ments, may cause ad­verse re­spons­es from the host’s im­mune sys­tem. Oth­er di­rec­tions of re­search in­clude di­rect­ly edit­ing dis­ease-caus­ing genes and ex­plor­ing the tech’s ap­pli­ca­tion in oth­er or­gans.

Elias Zerhouni (Photo by Vincent Isore/IP3/Getty Images)

Elias Zer­houni dis­cuss­es ‘am­a­teur hour’ in DC, the de­struc­tion of in­fec­tious dis­ease R&D and how we need to prep for the next time

Elias Zerhouni favors blunt talk, and in a recent discussion with NPR, the ex-Sanofi R&D and ex-NIH chief had some tough points to make regarding the pandemic response.

Rather than interpret them, I thought it would be best to provide snippets straight from the interview.

On the Trump administration response:

It was basically amateur hour. There is no central concept of operations for preparedness, for pandemics, period. This administration doesn’t want to or has no concept of what it takes to protect the American people and the world because it is codependent. You can’t close your borders and say, “OK, we’re going to be safe.” You’re not going to be able to do that in this world. So it’s a lack of vision, basically just a lack of understanding, of what it takes to protect the American people.

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George Yancopoulos (Regeneron)

Re­gen­eron co-founder George Yan­copou­los of­fers a com­bat­ive de­fense of the po­lice at a high school com­mence­ment. It didn’t go well

Typically, the commencement speech at Yorktown Central School District in Westchester — like most high schools — is an opportunity to encourage students to face the future with confidence and hope. Regeneron president and co-founder George Yancopoulos, though, went a different route.

In a fiery speech, the outspoken billionaire defended the police against the “prejudice and bias against law enforcement” that has erupted around the country in street protests from coast to coast. And for many who attended the commencement, Yancopoulos struck the wrong note at the wrong time, especially when he combatively challenged someone for interrupting his speech with a honk for “another act of cowardness.”

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Pfiz­er shares surge on pos­i­tive im­pact of their mR­NA Covid-19 vac­cine — part­nered with BioN­Tech — in an ear­ly-stage study

Pfizer and their partners at the mRNA specialist BioNTech have published the first glimpse of biomarker data from an early-stage study spotlighting the “robust immunogenicity” triggered by their Covid-19 vaccine, which is one of the leaders in the race to vanquish the global pandemic.

Researchers selected 45 healthy volunteers 18-55 years of age for the study. They were randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1, “a lipid nanoparticle-formulated, nucleoside-modified, mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein RBD.” Their responses were compared against the effect of a natural, presumably protective defense offered by a regular infection.

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An ex­pe­ri­enced biotech is stitched to­geth­er from transpa­cif­ic parts, with 265 staffers and a fo­cus on ‘new bi­ol­o­gy’

Over the past few years, different teams at a pair of US-based biotechs and in labs in Japan have labored to piece together a group of cancer drug programs, sharing a single corporate umbrella with research colleagues in Japan. But now their far-flung operations have been knit together into a single unit, creating a pipeline with 10 cancer drug development programs — going from early-stage right into Phase III — and a host of discovery projects managed by a collective staff of some 265 people.

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New stan­dard of care? FDA hands Pfiz­er, Mer­ck KGaA an OK for Baven­cio in blad­der can­cer

The breakthrough therapy designation Pfizer and Merck KGaA notched for Bavencio in bladder cancer has quickly paved way for a full approval.

The PD-L1 drug is now sanctioned as a first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma, applicable in cases where cancer hasn’t progressed after platinum-containing chemotherapy.

Petros Grivas, the principal investigator of the supporting Phase III JAVELIN Bladder 100, called the approval “one of the most significant advances in the treatment paradigm in this setting in 30 years.”

Sec­ond death trig­gers hold on Astel­las' $3B gene ther­a­py biotech's lead pro­gram, rais­ing fresh con­cerns about AAV

Seven months after Astellas shelled out $3 billion to acquire the gene therapy player Audentes, the biotech company’s lead program has been put on hold following the death of 2 patients taking a high dose of their treatment. And there was another serious adverse event recorded in the study as well, with a total of 3 “older” patients in the study affected.

The incidents are derailing plans to file for a near-term approval, which had been expected right about now.

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Randy Schatzman, Bolt CEO (Bolt Biotherapeutics)

Bolt Bio­ther­a­peu­tics nabs $93.5M to push Provenge in­ven­tor's new idea deep­er in the clin­ic

A cancer-fighting concept from the inventor of the first cancer vaccine is nearing prime time, and its biotech developer has received a significant new infusion of cash to get it there.

Bolt Biotherapeutics announced a $93.5 million Series C round led by Sofinnova Investments and joined by more than 9 others, including Pfizer Ventures and RA Capital Management. That money will go toward pushing the San Francisco biotech’s platform of innate immune-boosting warheads through its first trial on metastatic solid tumors and into several more.

Josh Cohen, Justin Klee

Armed with pos­i­tive ALS da­ta, Amy­lyx scores $30M in fresh fund­ing to com­plete Alzheimer's PhII

Four years after announcing themselves to the biotech world with a new idea for drugging neurodegeneration, backing by the late Henri Termeer and $5 million from Morningside Venture, the young entrepreneurs at Amylyx are back for round 2.

Morningside continued to lead the $30 million Series B, with participation from unnamed investors. Having celebrated a topline Phase II win for its lead program in amyotrophic lateral sclerosis, Amylyx expects the cash to fund talks with regulators as well as a separate trial for the same drug in Alzheimer’s — for which they had just finished enrolling.

Days af­ter In­ter­cept re­jec­tion, Akero surges on ‘un­prece­dent­ed‘ NASH da­ta

A year and a half after scoring a $70 million Series B and a top Gilead executive as CEO, Akero Therapeutics has announced new data on their NASH drug. And with the field still reeling from a surprise FDA rejection this week, the news was enough to send their stock surging.

Akero had already said in March that its lead drug had beaten placebo in its Phase II trial, reducing liver fat by 14% in the highest dose group compared to 0.3% in placebo, according to MRI scans. But although NASH is an obesity-related condition and results from fatty buildup in the liver, the real immediate question for any therapy is whether it can resolve the fibrosis and inflammation that results from that buildup. Those data require biopsying the patients, a longer and more invasive process that was further complicated by a pandemic.